tbuckley/cabot-search huggingface dataset:
Rapid Evolution of the Fine-scale Recombination Landscape in Wild House Mouse (<i>Mus musculus</i>) Populations
Authors: Lydia K Wooldridge, Beth L Dumont
Journal: Molecular Biology and Evolution (2022)

Abstract Meiotic recombination is an important evolutionary force and an essential meiotic process. In many species, recombination events concentrate into hotspots defined by the site-specific binding of PRMD9. Rapid evolution of Prdm9's zinc finger DNA-binding array leads to remarkably abrupt shifts in the genomic distribution of hotspots between species, but the question of how Prdm9 allelic variation shapes the landscape of recombination between populations remains less well understood. Wild house mice (Mus musculus) harbor exceptional Prdm9 diversity, with &amp;gt;150 alleles identified to date, and pose a particularly powerful system for addressing this open question. We employed a coalescent-based approach to construct broad- and fine-scale sex-averaged recombination maps from contemporary patterns of linkage disequilibrium in nine geographically isolated wild house mouse populations, including multiple populations from each of three subspecies. Comparing maps between wild mouse populations and subspecies reveals several themes. First, we report weak fine- and broad-scale recombination map conservation across subspecies and populations, with genetic divergence offering no clear prediction for recombination map divergence. Second, most hotspots are unique to one population, an outcome consistent with minimal sharing of Prdm9 alleles between surveyed populations. Finally, by contrasting aggregate hotspot activity on the X versus autosomes, we uncover evidence for population-specific differences in the degree and direction of sex dimorphism for recombination. Overall, our findings illuminate the variability of both the broad- and fine-scale recombination landscape in M. musculus and underscore the functional impact of Prdm9 allelic variation in wild mouse populations.
Associations Between Routine Adolescent Vaccination Status and Parental Intent to Get a COVID-19 Vaccine for Their Adolescent
Authors: Cassandra Pingali, Fan Zhang, Tammy A. Santibanez, Laurie D. Elam-Evans, Holly A. Hill, Madeleine R. Valier, James A. Singleton
Journal: JAMA Pediatrics (2022)

This cross-sectional study investigates whether US adolescents’ routine vaccination status is associated with their parents’ self-reported intent or hesitancy to have them vaccinated for COVID-19.
Ensuring Clarity and Understandability of the FDA’s Breast Density Notifications
Authors: Nancy R. Kressin, Priscilla J. Slanetz, Christine M. Gunn
Journal: JAMA (2022)

This Viewpoint discusses the use of breast density notifications to inform women with dense breast tissue of the potential need for supplemental cancer screening, as well as the need to ensure that such notifications are clear and understandable to women of all language backgrounds, literacy levels, educational levels, and socioeconomic backgrounds.
Radiotherapy Induces Innate Immune Responses in Patients Treated for Prostate Cancers
Authors: Amrita K. Cheema, Yaoxiang Li, Mary Ventimiglia, Keith Kowalczyk, Ryan Hankins, Gaurav Bandi, Einsley-Marie Janowski, Scott Grindrod, Alejandro Villagra, Anatoly Dritschilo
Journal: Clinical Cancer Research (2022)

Abstract Purpose: Radiotherapy is a curative therapeutic modality used to treat cancers as a single agent or in combination with surgery and chemotherapy. Advanced radiotherapy technologies enable treatment with large fractions and highly conformal radiation doses to effect free-radical damage to cellular DNA leading to cell-cycle arrest, cell death, and innate immune response (IIR) stimulation. Experimental Design: To understand systemic clinical responses after radiation exposure, proteomic and metabolomic analyses were performed on plasma obtained from patients with cancer at intervals after prostate stereotactic body radiotherapy. Pathway and multivariate analyses were used to delineate molecular alterations following radiotherapy and its correlation with clinical outcomes. Results: DNA damage response increased within the first hour after treatment and returned to baseline by 1 month. IIR signaling also increased within 1 hour of treatment but persisted for up to 3 months thereafter. Furthermore, robust IIR and metabolite elevations, consistent with an early proinflammatory M1-mediated innate immune activation, were observed in patients in remission, whereas patients experiencing prostate serum antigen–determined disease progression demonstrated less robust immune responses and M2-mediated metabolite elevations. Conclusions: To our knowledge, these data are the first report of longitudinal proteomic and metabolomic molecular responses in patients after radiotherapy for cancers. The data supports innate immune activation as a critical clinical response of patients receiving radiotherapy for prostate cancer. Furthermore, we propose that the observed IIR may be generalized to the treatment of other cancer types, potentially informing multidisciplinary therapeutic strategies for cancer treatment.
Craniocervical Junction Calcium Pyrophosphate Deposition Causing Hypoglossal Nerve Palsy
Authors: Javier Molina-Gil, Jorge Peña-Suárez, Carmen García-Cabo
Journal: JAMA Neurology (2022)

This case report describes an 80-year-old patient’s right-sided hemicranial headache, right-sided tongue hemiatrophy with fasciculations and deviation, right side of the tongue on protrusion, and mild dysarthria.
Multicenter Phase II Trial of the WEE1 Inhibitor Adavosertib in Refractory Solid Tumors Harboring <i>CCNE1</i> Amplification
Authors: Siqing Fu, Shuyang Yao, Yuan Yuan, Rebecca A. Previs, Anthony D. Elias, Richard D. Carvajal, Thomas J. George, Ying Yuan, Lihou Yu, Shannon N. Westin, Yan Xing, Ecaterina E. Dumbrava, Daniel D. Karp, Sarina A. Piha-Paul, Apostolia M. Tsimberidou, Jordi Rodon Ahnert, Naoko Takebe, Karen Lu, Khandan Keyomarsi, Funda Meric-Bernstam
Journal: Journal of Clinical Oncology (2022)

Preclinical cancer models harboring
Application of Nanotechnology in Thrombus Therapy
Authors: Shuyin Zhou, Wenbo Zhao, Jinglei Hu, Chun Mao, Min Zhou
Journal: Advanced Healthcare Materials (2022)

A thrombus is a blood clot that forms in the lumen of an artery or vein, restricting blood flow and causing clinical symptoms. Thrombosis is associated with many life-threatening cardiovascular diseases. However, current clinical therapeutic technologies still have many problems in targeting, enrichment, penetration, and safety to meet the thrombosis treatment needs. Therefore, researchers devote themselves to developing nanosystems loaded with antithrombotic drugs to address this paradox in recent years. Herein, the existing thrombosis treatment technologies are first reviewed; and then, their advantages and disadvantages are outlined based on a brief discussion of thrombosis's definition and formation mechanism. Furthermore, the need and application cases for introducing nanotechnology are discussed, focusing on thrombus-specific targeted ligand modification technology and microenvironment-triggered responsive drug release technology. Then, nanomaterials that can be used to design antithrombotic nanotherapeutic systems are summarized. Moreover, a variety of drug delivery technologies driven by nanomotors in thrombosis therapy is also introduced. Last of all, a prospective discussion on the future development of nanotechnology for thrombosis therapy is highlighted.
A Phase II Window of Opportunity Study of Neoadjuvant PD-L1 versus PD-L1 plus CTLA-4 Blockade for Patients with Malignant Pleural Mesothelioma
Authors: Hyun-Sung Lee, Hee-Jin Jang, Maheshwari Ramineni, Daniel Y. Wang, Daniela Ramos, Jong Min Choi, Taylor Splawn, Monica Espinoza, Michelle Almarez, Leandria Hosey, Eunji Jo, Susan Hilsenbeck, Christopher I. Amos, R. Taylor Ripley, Bryan M. Burt
Journal: Clinical Cancer Research (2022)

Abstract Purpose: We report the results of a phase II, randomized, window-of-opportunity trial of neoadjuvant durvalumab versus durvalumab plus tremelimumab followed by surgery in patients with resectable malignant pleural mesothelioma (MPM; NCT02592551). Patients and Methods: The primary objective was alteration of the intratumoral CD8/regulatory T cell (Treg) ratio after combination immune checkpoint blockade (ICB) therapy. Secondary and exploratory objectives included other changes in the tumor microenvironment, survival, safety, tumor pathologic response (PR), and systemic immune responses. Results: Nine patients received monotherapy and 11 received combination therapy. Seventeen of the 20 patients (85%) receiving ICB underwent planned thoracotomy. Both ICB regimens induced CD8 T-cell infiltration into MPM tumors but did not alter CD8/Treg ratios. At 34.1 months follow-up, patients receiving combination ICB had longer median overall survival (not reached) compared with those receiving monotherapy (14.0 months). Grade ≥3 immunotoxicity occurred in 8% of patients in the monotherapy group and 27% of patients in the combination group. Tumor PR occurred in 6 of 17 patients receiving ICB and thoracotomy (35.3%), among which major PR (&amp;gt;90% tumor regression) occurred in 2 (11.8%). Single-cell profiling of tumor, blood, and bone marrow revealed that combination ICB remodeled the immune contexture of MPM tumors; mobilized CD57+ effector memory T cells from the bone marrow to the circulation; and increased the formation of tertiary lymphoid structures in MPM tumors that were rich in CD57+ T cells. Conclusions: These data indicate that neoadjuvant durvalumab plus tremelimumab orchestrates de novo systemic immune responses that extend to the tumor microenvironment and correlate with favorable clinical outcomes.
Association of Direct-Acting Antiviral Therapy With Liver and Nonliver Complications and Long-term Mortality in Patients With Chronic Hepatitis C
Authors: Eiichi Ogawa, Nicholas Chien, Leslie Kam, Yee Hui Yeo, Fanpu Ji, Daniel Q. Huang, Ramsey Cheung, Mindie H. Nguyen
Journal: JAMA Internal Medicine (2022)

Chronic hepatitis C (CHC) and its complications are associated with high rates of morbidity and mortality. However, large-scale data analysis of the long-term liver and nonliver effects of direct-acting antiviral (DAA) treatment has been limited.To assess the association of hepatitis C virus elimination through DAA treatment with the risk of liver and nonliver morbidity and mortality during long-term follow-up among a large nationwide cohort of insured patients with CHC in the US.This was a retrospective cohort study of 245 596 adult patients with CHC using data from the Optum Clinformatics Data Mart database, 2010 to 2021. Of the total cohort, 40 654 patients had received 1 or more prescriptions for DAA medication (without interferon), and 204 942 patients were untreated.Treatment with a DAA.Incidence of hepatocellular carcinoma (HCC), liver decompensation, relevant nonliver events (nonliver cancer, diabetes, chronic kidney disease, cardiovascular disease), and overall mortality.The DAA-treated cohort (vs untreated) were older (mean [SD] age, 59.9 [10.8] vs 58.5 [13.0] years; P < .001); more likely to be male (25 060 [62%] vs 119 727 [58%] men; P < .001) and White (23 937 [59%] vs 115 973 [57%]; P < .001) individuals; and more likely to have diabetes (10 680 [26%] vs 52 091 [25%]; P < .001) or cirrhosis (17 971 [44%] vs 60 094 [29%]; P < .001). Comparing DAA-treated with untreated patients, the incidence (per 1000 person-years) of liver outcomes (eg, decompensation, 28.2 [95% CI, 27.0-29.4] vs 40.8 [95% CI, 40.1-41.5]; P < .001, and HCC in compensated cirrhosis, 20.1 [95% CI, 18.4-21.9] vs 41.8 [95% CI, 40.3-43.3]; P < .001) and nonliver outcomes (eg, diabetes, 30.2 [95% CI, 35.4-37.7] vs 37.2 [95% CI, 36.6-37.9]; P < .001; and chronic kidney disease, 31.1 [95% CI, 29.9-32.2] vs 34.1 [95% CI, 33.5-34.7]; P < .001) were significantly lower in treated patients. The all-cause mortality rates per 1000 person-years were also significantly lower in DAA-treated compared with untreated patients (mortality, 36.5 [95% CI, 35.4-37.7] vs 64.7 [95% CI, 63.9-65.4]; P < .001). In multivariable regression analysis, DAA treatment was independently associated with a significant decrease in the risk of liver (adjusted hazard ratio [aHR] for HCC, 0.73; decompensation, 0.36), nonliver (aHR for diabetes, 0.74; chronic kidney disease, 0.81; cardiovascular disease, 0.90; nonliver cancer, 0.89), and mortality outcomes (aHR, 0.43).The findings of this retrospective cohort study indicate that DAA treatment for insured patients with CHC was associated with improved liver- and nonliver outcomes, and ultimately, with long-term overall survival.
Molecular Subtypes of Head and Neck Cancer in Patients of African Ancestry
Authors: Nadia Mezghani, Alexandria Yao, Daria Vasilyeva, Nicole Kaplan, Austin Shackelford, Angela Yoon, Elizabeth Phillipone, Sunil Dubey, Gary K. Schwartz, Alison M. Taylor, Fatemeh Momen-Heravi
Journal: Clinical Cancer Research (2022)

Abstract Purpose: The purpose of this study was to better understand the complex molecular biomarkers and signatures of head and neck cancer (HNC) among Black patients and identify possible molecular changes associated with HNC disparities. Experimental Design: Molecular subtypes and genomic changes in HNC samples from patients of African and European ancestry in The Cancer Genome Atlas, Memorial Sloan Kettering Cancer Center, Broad Institute, MD Anderson Cancer Center, and John Hopkins University were identified. Molecular features (genomic, proteomic, transcriptomic) associated with race and genomic alterations associated with clinical outcomes were determined. An independent cohort of HNC tumor specimens was used to validate the primary findings using IHC. Results: Black patients were found to have a younger age at diagnosis, more aggressive tumor types, higher rates of metastasis, and worse survival compared with White patients. Black patients had fewer human papillomavirus–positive tumor types and higher frequencies of laryngeal subtype tumors. Higher frequencies of TP53, MYO18B, KMT2D, and UNC13C mutations and a lower frequency of PIK3CA mutations were observed in Black patients. Tumors of Black patients showed significant enrichment of c-MYC and RET-tyrosine signaling and amplifications. A significant increase in tumor expression of c-MYC in Black patients was observed and was associated with poor survival outcomes in the independent cohort. Conclusions: Novel genomic modifications and molecular signatures may be related to environmental, social, and behavioral factors associated with racial disparities in HNC. Unique tumor mutations and biological pathways have potential clinical utility in providing more targeted and individualized screening, diagnostic, and treatment modalities to improve health outcomes.
Longitudinal Associations Between Use of Mobile Devices for Calming and Emotional Reactivity and Executive Functioning in Children Aged 3 to 5 Years
Authors: Jenny S. Radesky, Niko Kaciroti, Heidi M. Weeks, Alexandria Schaller, Alison L. Miller
Journal: JAMA Pediatrics (2022)

Mobile devices are often used to keep young children occupied or calm, but it is not known whether this practice influences child development.To examine the longitudinal, bidirectional associations between the parent-reported frequency of using mobile devices to calm young children and children's executive functioning (EF) and emotional reactivity, testing moderation by child sex and temperament.This prospective cohort study included a community-based convenience sample of English-speaking parents of typically developing children aged 3 to 5 years. The study duration was from August 2018 to January 2020, with baseline (T1), 3-month follow-up (T2), and 6-month follow-up (T3) waves.Parent-reported frequency of use of mobile devices to calm children when upset (5-point Likert scale).At each wave, the child's EF was assessed with the Behavior Rating Inventory of Executive Function-Preschool Version Global Executive Composite and emotional reactivity with the Child Behavior Checklist Emotional Reactivity subscale. Structural equation models were built to examine cross-lagged associations of the use of devices for calming, EF, and emotional reactivity, testing for moderation by child sex or temperament (Child Behavior Questionnaire-Very Short Form surgency score, median split).Of 422 eligible parents with data at T1, 375 (88.9%) provided data at T2 and 366 (86.7%) at T3. At baseline, the mean (SD) age of the 422 children was 3.8 (0.5) years, the number of boys in the sample was 224 (53.1%), the number of individuals of non-Hispanic White race and ethnicity was 313 (74.2%), and among the parents, 254 (60.2%) had a college degree or higher. Among the boys, the use of devices to calm at T2 was associated with higher emotional reactivity at T3 (r [standardized regression coefficient] = 0.20; 95% CI, 0.10-0.30), while higher emotional reactivity at T2 had a nonsignificant association with increased device use for calming at T3 (r = 0.10; 95% CI, -0.01 to 0.21). Among children with high temperamental surgency, the use of devices to calm at T2 was associated with increased emotional reactivity at T3 (r = 0.11; 95% CI, 0.01-0.22), while higher emotional reactivity at T2 was associated with increased device use for calming at T3 (r = 0.13; 95% CI, 0.02-0.24).The findings of this study suggest that the frequent use of mobile devices for calming young children may displace their opportunities for learning emotion-regulation strategies over time; therefore, pediatric health care professionals may wish to encourage alternate calming approaches.
Non-invasive imaging biomarkers for liver steatosis in non-alcoholic fatty liver disease: present and future
Authors: Asako Nogami, Masato Yoneda, Michihiro Iwaki, Takashi Kobayashi, Yasushi Honda, Yuji Ogawa, Kento Imajo, Satoru Saito, Atsushi Nakajima
Journal: Clinical and Molecular Hepatology (2022)

Non-alcoholic fatty liver disease is currently the most common chronic liver disease, affecting up to 25% of the global population. Simple fatty liver, in which fat is deposited in the liver without fibrosis, has been regarded as a benign disease in the past, but it is now known to be prognostic. In the future, more emphasis should be placed on the quantification of liver fat. Traditionally, fatty liver has been assessed by histological evaluation, which requires an invasive examination; however, technological innovations have made it possible to evaluate fatty liver by non-invasive imaging methods, such as ultrasonography, computed tomography, and magnetic resonance imaging. In addition, quantitative as well as qualitative measurements for the detection of fatty liver have become available. In this review, we summarize the currently used qualitative evaluations of fatty liver and discuss quantitative evaluations that are expected to further develop in the future.
Cardiac metabolism in HFpEF: from fuel to signalling
Authors: Federico Capone, Cristian Sotomayor-Flores, David Bode, Rongling Wang, Daniele Rodolico, Stefano Strocchi, Gabriele G Schiattarella
Journal: Cardiovascular Research (2022)

Heart failure (HF) is marked by distinctive changes in myocardial uptake and utilization of energy substrates. Among the different types of HF, HF with preserved ejection fraction (HFpEF) is a highly prevalent, complex, and heterogeneous condition for which metabolic derangements seem to dictate disease progression. Changes in intermediate metabolism in cardiometabolic HFpEF-among the most prevalent forms of HFpEF-have a large impact both on energy provision and on a number of signalling pathways in the heart. This dual, metabolic vs. signalling, role is played in particular by long-chain fatty acids (LCFAs) and short-chain carbon sources [namely, short-chain fatty acids (SCFAs) and ketone bodies (KBs)]. LCFAs are key fuels for the heart, but their excess can be harmful, as in the case of toxic accumulation of lipid by-products (i.e. lipotoxicity). SCFAs and KBs have been proposed as a potential major, alternative source of energy in HFpEF. At the same time, both LCFAs and short-chain carbon sources are substrate for protein post-translational modifications and other forms of direct and indirect signalling of pivotal importance in HFpEF pathogenesis. An in-depth molecular understanding of the biological functions of energy substrates and their signalling role will be instrumental in the development of novel therapeutic approaches to HFpEF. Here, we summarize the current evidence on changes in energy metabolism in HFpEF, discuss the signalling role of intermediate metabolites through, at least in part, their fate as substrates for post-translational modifications, and highlight clinical and translational challenges around metabolic therapy in HFpEF.
Molecular Mechanisms of PTH/PTHrP Class B GPCR Signaling and Pharmacological Implications
Authors: Jean-Pierre Vilardaga, Lisa J Clark, Alex D White, Ieva Sutkeviciute, Ji Young Lee, Ivet Bahar
Journal: Endocrine Reviews (2022)

The classical paradigm of G protein-coupled receptor (GPCR) signaling via G proteins is grounded in a view that downstream responses are relatively transient and confined to the cell surface, but this notion has been revised in recent years following the identification of several receptors that engage in sustained signaling responses from subcellular compartments following internalization of the ligand-receptor complex. This phenomenon was initially discovered for the parathyroid hormone (PTH) type 1 receptor (PTH1R), a vital GPCR for maintaining normal calcium and phosphate levels in the body with the paradoxical ability to build or break down bone in response to PTH binding. The diverse biological processes regulated by this receptor are thought to depend on its capacity to mediate diverse modes of cyclic adenosine monophosphate (cAMP) signaling. These include transient signaling at the plasma membrane and sustained signaling from internalized PTH1R within early endosomes mediated by PTH. Here we discuss recent structural, cell signaling, and in vivo studies that unveil potential pharmacological outputs of the spatial versus temporal dimension of PTH1R signaling via cAMP. Notably, the combination of molecular dynamics simulations and elastic network model-based methods revealed how precise modulation of PTH signaling responses is achieved through structure-encoded allosteric coupling within the receptor and between the peptide hormone binding site and the G protein coupling interface. The implications of recent findings are now being explored for addressing key questions on how location bias in receptor signaling contributes to pharmacological functions, and how to drug a difficult target such as the PTH1R toward discovering nonpeptidic small molecule candidates for the treatment of metabolic bone and mineral diseases.